Mechanism and Synergy of gamma-Secretase Modulators

 描述(申请人提供)：这项建议的总体目标是阐明不同类别的下一代γ分泌酶调节剂(GSM)的作用机制，确定它们的协同作用，并将它们应用于研究Aβ42、Aβ38和Aβ37在淀粉样蛋白病理、突触可塑性和学习记忆中的作用。GSM的开发可以抑制Aγ-β42的分泌酶活性，但不影响APP的整体加工和其他底物的切割，已成为治疗AD的一种有前景的策略。这些临床候选药物的开发进展取决于对药物-靶点相互作用的更深入了解。为此，我们建议在γ-分泌酶复合体中定位酸性GSM的结合位置，并研究γ-分泌酶调控的结构基础。此外，我们还将确定γ分泌酶活性位点和基于咪唑的GSM结合位点(S)之间的协同作用机制。最后，我们将考察两类GSM在细胞和动物模型中的协同效应，重点是安全性、突触可塑性和学习记忆。这项拟议的研究将为GSM对γ-分泌酶的调节、Aβ在疾病中的作用和新的治疗策略提供机械性的见解，形成我们对GSM选择性的理解，并提高我们设计有效治疗的能力。

 DESCRIPTION (provided by applicant): The overall objectives of this proposal are to elucidate the mechanism of action of different classes of next generation γ-secretase modulators (GSMs), to determine their synergistic effect, and to apply them in examining the role of Aβ42, Aβ38 and Aβ37 in amyloid pathology, synaptic plasticity and learning and memory. The development of GSMs that suppress γ-secretase activity for Aβ42 production and yet do not affect overall APP processing and cleavages of other substrates has emerged as a promising strategy for AD therapy. Progress in the development of these clinical candidates depends on a deeper understanding of the drug-target interactions. To this end we propose to map the binding site of acid GSMs within the γ-secretase complex and to investigate the structural basis of γ-secretase modulation. Additionally, we will determine the mechanism of cooperatively between the γ-secretase active site and the imidazole based GSM binding site(s). Finally, we will examine the synergistic effect of two classes of GSMs in cellular and animal models with a focus on safety, synaptic plasticity and learning and memory. The proposed research will provide mechanistic insights into GSM modulation of γ-secretase, the function of Aβ in disease and new therapeutic strategies, shaping our understanding of GSM selectivity and advancing our ability to design effective treatment.